A clinical assay for the measurement of milrinone in plasma by HPLC mass spectrometry

Milrinone is a bipyridine phosphodiesterase inhibitor with positive inotropic and vasodilatory effects. As interest in longer term use of intravenous therapy increases, it becomes essential to monitor its plasma concentration owing to a narrow therapeutic range, an increased half-life in renal failure and toxicity associated with high levels. A high-performance liquid chromatography (HPLC) method with mass (MS) detection using a triple quadrupole mass spectrometer is presented. The method was compared with the UV/HPLC method and validated according to current international guidelines. Coefficients of variation of less than 7.5% were obtained across the therapeutic range and 18.3% at 2.4 ng/mL, the lower limit of quantitation. Plasma from 13 cardiac surgery patients receiving standard intravenous doses of milrinone were measured. Eight patients achieved therapeutic milrinone levels within 3-4 h post start of infusion, one was borderline sub-therapeutic and four patients achieved levels that were above the upper limit of the therapeutic range and potentially toxic. This method offers high sensitivity, is rapid, easy to use and requires minimal amount of sample. We believe this method could become the reference procedure for clinical monitoring of milrinone and help to improve the safety of the use of this drug in patients with cardiac failure.     

Comparison of a RP-HPLC Method with the Therapeutic Drug Monitoring System TDx for the Determination of Theophylline in Blood Serum

Abstract

Blood serum samples of patients undergoing theophylline therapy were analysed in parallel with a new RP-HPLC method and the therapeutic drug monitoring TDx system. Both techniques are accurate, precise, technically easy, rapid, but the results taken by the TDx method are in all cases higher than HPLC. The mean increase is of about 56%.     

Rapid liquid chromatography-tandem mass spectrometry method for quantification of ziprasidone in human plasma

A liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the determination of ziprasidone (ZIP) in human plasma was developed. ZIP and N-methyl ziprasidone as internal standard (IS) were extracted from alkalinized plasma using tert- butyl methyl ether. Separation was performed isocratically on a C8 column with 90% acetonitrile containing 2 mmol/L ammonium acetate as a mobile phase with a total run time of 2.5 min. MS/MS transitions of m/z 413 --> 194 and m/z 427 --> 177 of the analyte and internal standard were used for quantification. Confirmatory ions of m/z 413 --> 177 and m/z 427 --> 180 were collected as well. The calibration curve based on peak-area ratio was linear up to at least 200 ng/mL with a detection limit of 0.1 ng/mL. The method showed satisfactory reproducibility with a coefficient of variation of less than 5%. The method was successfully applied to the analysis of ZIP in spiked human plasma.     

企业联盟发展的力学分析与联盟策略

企业联盟能通过资源共享促进企业可持续竞争优势形成和企业成长。企业联盟成长包括联盟运行和联盟发展两个维度,企业联盟发展受联盟力的影响,而联盟企业、联盟力及其作用效果满足经典力学理论,据此构建企业联盟发展的力学模型,并通过对其公式推导,得到企业联盟发展的四大定理——"偏利共生"定理、"宇称不对称"定理、"大数中心"定理和"动态自稳定"定理及相关推论,而算例分析也对定理进行了验证,最后,相应提出了企业联盟发展的联盟网络、领先跟随、动态平衡与选择培育策略。     

nurP28, a New-to-Nature Zein-Derived Peptide,Enhances the Therapeutic Effect of Docetaxel in Breast Cancer Monolayers and Spheroids

The development of novel cancer therapeutic strategies has garnered increasing interest in cancer research. Among the therapeutic choices, chemosensitizers have shown exciting prospects. Peptides are an attractive alternative among the molecules that may be used as chemosensitizers. We rationally designed a new-to-nature peptide, nurP28, derived from the 22-kDa α-zein protein sequence (entry Q00919_MAIZE). The resultant sequence of the nurP28 peptide after the addition of arginine residues was LALLALLRLRRRATTAFIIP, and we added acetyl and amide groups at the N- and C-terminus, respectively, for capping. We evaluated the cytotoxicity of the nurP28 peptide alone and in combination with docetaxel in fibroblast monolayers and breast cancer monolayers and spheroids. Our results indicated that nurP28 is not cytotoxic to human fibroblasts or cancer cells. Nevertheless, when combined with 1 µM docetaxel, 3 ng/mL nurP28 induced equivalent (in MCF7 monolayers) and higher (in MCF7 spheroids) cytotoxic effects than 10-fold higher doses of docetaxel alone. These findings suggest that nurP28 may act as a chemosensitizer in breast cancer treatment. This study describes the enhancing “anti-cancer” effects of nurP28 in breast cancer 2D and 3D cultures treated with docetaxel. Further studies should explore the mechanisms underlying these effects and assess the clinical potential of our findings using animal models.     

动态联盟环境下准时生产技术应用与研究

提出了一种动态联盟环境下实现准时生产管理的技术。以动态联盟为基础建立面向订单的虚拟工厂,按MRPⅡ理论制订虚拟工厂的生产计划,对之作分解后分发到联盟中的各成员企业。在成员企业中围绕联盟下达的生产计划采用JIT技术进行生产控制,从而发挥动态联盟协同生产计划和符合准时化要求的企业生产系统各自的优势,有效地提高企业竞争力。     

A High-Throughput Clinical Laboratory Methodology for the Therapeutic Monitoring of Ibrutinib and Dihydrodiol Ibrutinib

Ibrutinib (IBR) is an oral anticancer medication that inhibits Bruton tyrosine kinase irreversibly. Due to the high risk of adverse effects and its pharmacokinetic variability, the safe and effective use of IBR is expected to be facilitated by precision dosing. Delivering suitable clinical laboratory information on IBR is a prerequisite of constructing fit-for-purpose population and individual pharmacokinetic models. The validation of a dedicated high-throughput method using liquid chromatography–mass spectrometry is presented for the simultaneous analysis of IBR and its pharmacologically active metabolite dihydrodiol ibrutinib (DIB) in human plasma. The 6 h benchtop stability of IBR, DIB, and the active moiety (IBR + DIB) was assessed in whole blood and in plasma to identify any risk of degradation before samples reach the laboratory. In addition, four regression algorithms were tested to determine the optimal assay error equations of IBR, DIB, and the active moiety, which are essential for the correct estimation of the error of their future nonparametric pharmacokinetic models. The noncompartmental pharmacokinetic properties of IBR and the active moiety were evaluated in three patients diagnosed with chronic lymphocytic leukemia to provide a proof of concept. The presented methodology allows clinical laboratories to efficiently support pharmacokinetics-based precision pharmacotherapy with IBR.     

Oxidative Stress and Antioxidative Therapy in Pulmonary Arterial Hypertension

Pulmonary arterial hypertension (PAH) is clinically characterized by a progressive increase in pulmonary artery pressure, followed by right ventricular hypertrophy and subsequently right heart failure. The underlying mechanism of PAH includes endothelial dysfunction and intimal smooth muscle proliferation. Numerous studies have shown that oxidative stress is critical in the pathophysiology of PAH and involves changes in reactive oxygen species (ROS), reactive nitrogen (RNS), and nitric oxide (NO) signaling pathways. Disrupted ROS and NO signaling pathways cause the proliferation of pulmonary arterial endothelial cells (PAECs) and pulmonary vascular smooth muscle cells (PASMCs), resulting in DNA damage, metabolic abnormalities, and vascular remodeling. Antioxidant treatment has become a main area of research for the treatment of PAH. This review mainly introduces oxidative stress in the pathogenesis of PAH and antioxidative therapies and explains why targeting oxidative stress is a valid strategy for PAH treatment.     

产业技术创新联盟成员竞合关系管理 ——基于产业技术创新联盟调查问卷的分析

在动态创新环境中,企业间已由单纯的竞争关系转向竞争和合作并存的关系,这种转变对于企业创新产生了很大影响,带来了许多新的管理问题。产业技术创新联盟成员间也存在这种竞合关系,对联盟成员间竞合关系进行有效的管理有助于提高联盟整体的创新绩效,促进联盟实现协同价值。本文利用我们开展产业技术创新联盟调查获得的数据,剖析了影响联盟成员间竞争与合作关系的因素,针对加强联盟成员竞合关系管理、提升合作创新绩效提出了具体的对策建议。